1. Field of the Invention
The present invention relates to amino substituted steroids which are useful as pharmaceutical agents.
2. Description of the Related Art
Various amino (substituted) steroids are known with the amine substitution on either the steroidal ring system or on the side chain of the D-ring at C.sub.17.
U.S. Pat. No. 4,456,602 discloses steroidal 21-esters in which there is an amino function in the non-steroidal portion of the ester.
In the 3.alpha.-hydroxy series, U.S. Pat. No. 3,998,829 discloses 21-aminomethyl steroids and U.S. Pat. No. 3,983,111 discloses 21-amino steroids where the amino group is cyclized. These patents also disclose reduced A-ring steroids as well as steroids with a hydrogen atom at C.sub.17 and two hydrogen atoms at C.sub.11.
20-Amino steroids are known in the .DELTA..sup.4 -3-keto series with no substitution at C.sub.11 and C.sub.17, see Can. J. Chem., 47, 160 (1969); J. Med. Chem., 27, 1690 (1983); U.S. Pat. Nos. 4,377,584 and 4,191,759; Chem.-Biol. Interact., 46, 1 (1983); J. Steroid Biochem., 20, 1095 (1984); Inorg. Chim. Acta, 91, 257 (1984), with substitution at C.sub.11, see Steroids 35, 265 (1980) and Biochim. Biophys. Acta, 623, 280 (1980) as well as with substitution at both C.sub.11 and C.sub.17, see Steroids, supra.
20-Amino steroids are known in the .DELTA..sup.1,4 -3-keto series with an 11.beta.-hydroxyl substitution, see Steroids, supra, as well as with 11.beta.,17.alpha.-dihydroxy substitution, see Protides Biol. Fluids, 29, 393 (1982); J. Clin. Chem. Clin. Biochem., 22, 209 (1984); Eur. J. Biochem., 108, 47 (1980); J. Steroid Biochem., 14, 697 (1981), Nature (London) 279, 158 (1979) and Eur. J. Biochem., 131, 333 (1983) and with 11.alpha.,17.alpha.-dihydroxy substitution, see J. Clin. Chem. Clin. Biochem.21, 69 (1983). U.S. Pat. No. 4,191,759 discloses 20-amino.DELTA..sup.1,4 -3-keto steroids without any substitution at the 11 position where the amine substituent is morpholine or piperazine.
21-Amino steroids are known in the .DELTA..sup.4 -3-keto series with no substitution at C.sub.11, see J. Org. Chem., 45, 3084 (1980); J. Org. Chem., 26, 1223 and 5052 (1961); J. Chem. Soc., Perkin Trans. 1, 502 (1972); Great Britain Patent 954,146 and its U.S. equivalent, U.S. Pat. No. 3,123,598; Austrian Patent 249,883; Arch. Biochem. Biophys., 182, 197 (1977) and Khim.-Farm. 2, 26 (1968). In addition 21-amino steroids are known in the .DELTA..sup.1,4 -3-keto series substituted with 11.beta.-hydroxyl, see Arch. Biochem. Biophys., 182, 197 (1977); Int. Conf. Chem. Biotechnol. Biol. Act. Nat. Prod. 2, 135-49 (1981); Analyst (London) 98, 519 (1972); U.S. Pat. Nos. 3,705,150, 4,076,737 and 2,920,999; Nature, 191, 607 (1961); Hungarian Patent 150,350 and J. Org. Chem., 45, 3084 (1980). For example Hungarian Patent 150,350 discloses dipersolone, 11.beta.,17.alpha.-dihydroxy-21-(4-methyl-1-piperazinyl)pregna-1,4-diene-3 ,20-dione. Further, U.S. Pat. No. 3,705,150 discloses 21-[N-(N'-methyl)piperazinyl]prednisolone.
German Patent 1,087,598 and U.S. Pat. No. 2,920,999 disclose simple 21-amino derivatives of .DELTA..sup.4 -3-keto steroids. The amines include both mono and bis substituted amines. In the cases where the amino group is disubstituted, the two substituents can be cyclized with the attached nitrogen atom to form a heterocyclic amino group (morpholine, pyrrolidine, piperidine, pyridine). The amines were chosen from the group consisting of amino, monoalkylamino, dialkylamino, phenylamino, pyridylamino, benzylamino, picolinylamino, N-alkyl-N-phenylamino, N-alkyl-N-pyridylamino, morpholinyl, pyrryl, pyrrolidyl, piperidino and C-alkylated piperidino, though only N-piperidino, N,N-diethyl and N-methyl-N-phenyl were exemplified. The amino steroids of the present invention while containing the steroid portion of the compounds of U.S. Pat. No. 2,920,999, contain more complex amines.
U.S. Pat. No. 3,144,446 discloses mono and bis quaternary ammonium salts of triethylenediamine. The amines and amino steroids of the present invention do not include triethylenediamine or other bridged amine, only 1-piperazinyl substituted amines.
U.S. Pat. No. 2,665,274 discloses pyridium salts of steroids. In the present invention R.sub.21 and R.sub.210 are taken together with the attached carbon atom to form a heterocyclic ring but not an aromatic ring.
Chem. Abst. 70, 115402v (1969) discloses amino steroids where the amines are morpholino, piperidino and dimethyl. The amines of the amino steroids of the present invention are much more complex than these three simple unsubstituted amines.
A number of 20-amino steroids are known where the 20-amino group is of the general type --NH--(CH.sub.2).sub.x --N(R.sub.1)(R.sub.2) where x is 2 or 3 and R.sub.1 and R.sub.2 are methyl or ethyl. See, for example, Arch. Farmacol. Toxicol. 4, 265 (1978), Lipids, 2, 5 (1967), J. Med. Chem. 15, 1129 (1972), ibid 15, 1284 (1972), French Patent 90805, Lipids 11, 616 (1976), U.S. Pat. No. 3,558,608, Chem. Abst. 62, 14784a, ibid 64, 14573e, ibid 65, 2334d, ibid 56, 15583a, b, and i, ibid 57, 12574d, ibid 57, 6225d.
Many 20-amino and 21-amino steroids are known where the amino group is substituted with simple alkyl (C.sub.1 -C.sub.3), aryl (phenyl), simple aralkyl (benzyl), as well as substituents containing hetero atoms (sulfur), esters, acids, amino substituted alkyl, alcohols, ethynyl groups, etc. The amino steroids are known where the amine portion is either mono or disubstituted. In the cases where the amino group is disubstituted, the two substituents can be cyclized with the attached nitrogen atom to form a heterocyclic amino group. These simple cyclic and heterocyclic amines, see U.S. Pat. Nos. 3,523,942, 4,191,759 and 2,920,999, are unlike the complex amine substituents of the present invention. The known 21-amino substituted steroids include simple (substituted) cyclic amines such as 4-(2-hydroxyethyl)-1-piperazinyl [CA 65;20189g]; 4-(2-hydroxyethyl)-1-piperidinyl [83544-11-0]; 4,4-dimethyl-1-piperazinyl, 3-hydroxyethyl-1-piperidinyl, 4-hydroxy-1-piperidinyl, 4-carboxy-1-piperidinyl, 3-hydroxy-1-piperidinyl, 3-carboxy-1-piperidinyl, piperazinyl, bis(hydroxyethyl)amino, 4-acetyl-1-piperazinyl, 4-carboxaldehyde-1-piperazinyl, 1-piperidinyl, [Int. Conf. Chem. Biotechnol. Biol. Act. Nat. Prod. [Proc.]1st. Vol. 2, p. 135, 1981]; 4-methyl-1-piperazinyl [Great Britain Patent 2,136,293]; 3,6-dihydro-2,6-dioxo-1(2H)-pyrimidinyl, 5-fluoro-3,6-dihydro-2,6-dioxo-1(2H)-pyrimidinyl, 5-fluoro-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl, 3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl, 3,4-dihydro-5-methyl-2,4-dioxo-1(2H)-pyrimidinyl [J. Steroid Biochem. 9, 1155 (1978)]; and 4-morpholinyl [J. Chem. Soc. Perkin Trans I, 502 (1972)].
U.S. Pat. No. 3,697,509 discloses .DELTA..sup.17(20) -21-quaternary amino steroid salts. The .DELTA..sup.17(20) -21-amino steroids (V) of the present invention include pharmaceutically acceptable salts, but not quaternary amine salts.
Japanese published application J8 5043068 discloses azepino(1,2,3-1H)-.beta.-carboline derivatives which inhibit lipid peroxidation and are useful in inhibiting the aging of living bodies.
Some of the free amines of the amino substituent of the amino substituted steroids (XI) of the present invention are known. See, for example, U.S. Pat. No. 4,492,696.
While some of the free amines of the amino steroids of the present invention are known, such as 2-carboxy-1-piperidine [Aldrich, item P4,585-0], 4-(2-pyridinyl)piperazine [French Patent 7253 M], 4-(2-pyridinylmethyl)piperazine [European Patent application 49,683], 4-(6-methoxy-2-pyridinyl)piperazine [Canadian Patent 679,894], 4-(2-pyrimidinyl)piperazine [U.S. Pat. No. 4,409,223], 4-(3,6-dimethylpyrazinyl)piperazine [Canadian Patent 979,894], 4-(2-methoxy-phenyl)piperazine [Aldrich, item M2,260-1], 4-(4-methoxyphenyl)-piperazine [Aldrich item M2,300-4], 4-[(3,4-dimethoxyphenyl)methyl]piperazine [French Patent 7031 M], 4-(4-fluorophenyl)piperazine [Aldrich, item 19,133-7], 4-[[4-(dimethylamino)phenyl]methyl]piperazine [U.S. Pat. No. 4,421,753], 4-hydroxy-4-[4-(trifluoromethyl)phenyl]piperazine [U.S. Pat. No. 3,936,464], (2-diethylaminoethyl)amine [Aldrich, item 12,694-2], [2-(3,4-dimethoxyphenyl)ethyl]amine [Aldrich, item D13,620-4], [2-(2,4-dimethoxyphenyl)-1-methylethyl]amine [J. Pharm. Sci. 60, 1232 (1971)], [2-(3,4-dimethoxyphenyl)ethyl][[4-dimethylamino)phenyl]methyl]amine [Chem. Abst. 65:7001f] and (2-pyridinyl)methylamine [Aldrich, item A6,520-4], most are novel.
Great Britain Patent 1,345,640 and U.S. Pat. No. 3,835,132 generically disclose piperazinyl substituted pyrimidines including those where the substituents are morpholino, monoalkylamino, cycloalkyl, N-benzylpiperazino, --NEt.sub.2, --NHCH.sub.2 CH.sub.2 OH and piperazino. Specifically disclosed are 4-[2-morpholino-6-ethylamino-4-pyrimidinyl]piperazine (named the same way the amines of the present invention are named), see Example 1 and 4-[4-morpholino-2-ethylamino-4-pyrimidinyl]piperazine, see Example 2.
Great Britain Patent 1,390,014 and U.S. Pat. No. 3,980,650 disclose 4-aminoquinazolines. The starting material for Example VI is 1-cyano-4-(2-furoyl)piperazine, N.tbd.C-piperazine-(2-furoyl). One of the amines of the present invention is 4-(2-furanylcarbonyl)piperazine, see PREPARATION A-3. The amine of the present invention differs from the prior art amine in that it does not have a cyano group and does not have a carbonyl group between the piperazine and the furoyl substituent.
Chem. Abst. 85, 78082c (1976) discloses 4-(2-furoyl)piperazine, 4-(2-thienyl)piperazine and 4-(3-thienyl)piperazine. The present invention includes 4-(2-furanylcarbonyl)piperazine, see PREPARATION A-3. The amine of the present invention differs from the prior art compounds in that they do not include the thienyl moiety or do have a carbonyl group separating the piperazine from the furoyl group.
French Patent 1,413,722 and U.S. Pat. Nos. 3,325,496 and 3,374,173 disclose 2,4,6-triamino-substituted pyrimidines including bis(dialkylamino)piperidino substituted pyrimidine. The present invention includes piperazinyl substituted pyrimidines, not piperidino substituted pyrimidines.
Most of the steroidal 21-(hydroxy derivative) halo (bromine or iodine), mesylate or tosylate starting materials are known, such as
21-bromo-17.alpha.-hydroxypregna-4,9-diene-3,20-dione [U.S. Pat. No. 4,041,055 (Ex 59)], PA0 21-bromo-17.alpha.-hydroxypregn-4-ene-3,11,20-trione [J. Chem. Soc. B., 4, 748 (1970)], PA0 11.alpha.,21-dihydroxypregn-4-ene-3,20-dione [U.S. Pat. No. 4,013,688], PA0 21-bromo-17.alpha.-hydroxypregn-4-ene-3,20-dione [U.S. Pat. No. 4,500,461], PA0 21-bromopregn-4-ene-3,11,20-trione [U.S. Pat. No. 3,983,111], PA0 21-hydroxypregna-4,9(11),16-triene-3,20-dione [Tetrahedron Lett. 25, 2581 (1984)], PA0 21-iodopregna-4,9(11)-diene-3,20-dione [95288-91-8], PA0 21-bromopregn-4-ene-3,20-dione [J. Org. Chem., 50, 81 (1985), PA0 11.beta.,17.alpha.-dihydroxy-21-iodo-6.alpha.-methylpregna-1,4-diene-3,20-d ione [J. Pharm. Soc., 74, 365 (1985)], PA0 21-bromo-11.beta.,17.alpha.-dihydroxypregna-1,4-diene-3,20-dione [U.S. Pat. No. 3,856,956], PA0 17.alpha.-hydroxy-21-iodo-16.alpha.-methylpregna-1,4,9(11)-triene-3,20-dion e [U.S. Pat. No. 3,455,968], PA0 17.alpha.,21-dihydroxy-6.alpha.-methylpregna-1,4,9(11)-triene-3,20-dione [West German DE 3,322,120], PA0 17.alpha.-Hydroxy-21-iodopregna-1,4-diene-3,11,20-trione [J. Med. Chem., 28, 171 (1985)], PA0 21-bromopregna-1,4-diene-3,20-dione [Bull. Chem. Soc. Jpn. 58, 981 (1985)], PA0 17.alpha.,21-dihydroxypregna-1,4,9(11)-triene-3,20-dione [West German DE 3,322,120], PA0 17.alpha.,21-dihydroxy-16.beta.-methyl-5.alpha.-pregn-9(11)-ene-3,20-dione [U.S. Pat. No. 4,336,200] and PA0 21-bromo-3.alpha.,17.alpha.-dihydroxy-5.beta.-pregnane-11,20-dione ]95044-38-5], however some are novel. PA0 (A) C.sub.1 -C.sub.3 alkyl, PA0 (B) C.sub.1 -C.sub.12 alkoxy, PA0 (C) furanyl, PA0 (D) --NR.sub.122 R.sub.123, where one of R.sub.122 and R.sub.123 is --H, methyl or ethyl and the other is --H, C.sub.1 -C.sub.4 alkyl or phenyl, PA0 (A) R.sub.21 is PA0 (B) R.sub.210 is PA0 (C) R.sub.21 and R.sub.210 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of PA0 (I) one of R.sub.161 or R.sub.162 is taken together with one of R.sub.171 or R.sub.172 to form a second bond between C.sub.16 and C.sub.17, only when R.sub.10 is .alpha.-R.sub.101 :.beta.-R.sub.102, .alpha.-R.sub.103 : .beta.-R.sub.104, .alpha.-R.sub.107 :.beta.R.sub.108 or .alpha.-R.sub.109 :.beta.-R.sub.1010, PA0 (II) R.sub.17 is .dbd.CH--(CH.sub.2 (.sub.p --NR.sub.21 R.sub.210, only when R.sub.10 is a .alpha.-R.sub.101 :.beta.-R.sub.102, .alpha.-R.sub.103 :.beta.-R.sub.104, .alpha.-R.sub.107 :.beta.-R.sub.108 or .alpha.-R.sub.109 :.beta.-R.sub.1010, PA0 (III) R.sub.5 and R.sub.10 taken together are .dbd.CH--CH.dbd.C(OR.sub.3)--CH.dbd., only when R.sub.17 is .alpha.-R.sub.175 :.beta.-R.sub.176 or the 16,17-acetonide of a compound where R.sub.16 is .alpha.-OH:.beta.-H and R.sub.17 is .alpha.-OH:.beta.-C(.dbd.Z(--(CH.sub.2).sub.n --NR.sub.21 R.sub.210, and PA0 (IV) R.sub.5 is .alpha.-R.sub.57 :.beta.-R.sub.58, only when R.sub.17 is .alpha.-R.sub.175 :.beta.-R.sub.176 or .alpha.-OH:.beta.-C--(.dbd.Z)--(CH.sub.2).sub.n --NR.sub.21 R.sub.210, or the 16,17-acetonide thereof. PA0 (A) C.sub.1 -C.sub.3 alkyl, PA0 (B) C.sub.1 -C.sub.12 alkoxy, PA0 (C) furanyl, PA0 (D) --NR.sub.122 R.sub.123, where one of R.sub.122 and R.sub.123 is --H, methyl or ethyl and the other is --H, C.sub.1 -C.sub.4 alkyl or phenyl, PA0 (E) --X.sub.3 --X.sub.1, where X.sub.3 is --O-- or a valence bond, where X.sub.1 is phenyl optionally substituted with 1 through 2 --Cl, C.sub.1 -C.sub.3 alkoxy, --NH.sub.2, C.sub.1 -C.sub.3 alkylamino, di(C.sub.1 -C.sub.3)alkylamino, where the alkyl groups are the same or different, 1-pyrrolidinyl-, 1-piperdinyl, C.sub.2 -C.sub.4 acylamino and --NH--CHO; PA0 (C) R.sub.21 and R.sub.210 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of PA0 (D-III) R.sub.16 is .alpha.-R.sub.165 :.beta.-R.sub.166 and R.sub.17 is .alpha.-R.sub.175 :.beta.-R.sub.176, where R.sub.165 is --H, --OH, --F or --CH.sub.3 and R.sub.166 is --H, --OH, --F, or --CH.sub.3, with the proviso that at least one of R.sub.165 and R.sub.166 is --H, where R.sub.175 is --H, --OH, --CH.sub.3, --CH.sub.2 CH.sub.3, C.sub.2 -C.sub.7 alkanoyloxy or --O--CO--X.sub.1, where X.sub.1 is as defined above, and where R.sub.176 is --C(.dbd.Z)--(CH.sub.2).sub.n --NR.sub.21 R.sub.210, where Z is .dbd.O, .dbd.CH.sub.2 or R.sub.179 :--H, where R.sub.179 is --H or --CH.sub.3, where n is 1, where PA0 (C) R.sub.21 and R.sub.210 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of PA0 21-[4-[3,6-bis(diethylamino)-2-pyridinyl]-1-piperazinyl]-16.alpha.-methylpr egna-1,4,9(11)-triene-3,20- dione and PA0 21-[4-[6-(ethylamino)-2-pyridinyl]piperazinyl]-16.alpha.-methylpregna-1,4,9 (11)-triene-3,20-dione. PA0 1-(4-methyl)-piperazinyl, [J-1] PA0 1-(4-acetyl)-piperazinyl, ]J-2] PA0 1-(4-hydroxy)-piperidinyl [J-3] PA0 1-piperidinyl optionally substituted with PA0 2-hydroxyethyl, [J-4] PA0 4-morpholino [J-5]